There is growing evidence that the basal ganglia (BG) participate in multiple segregated "loops" with a wide variety of cortical areas including regions of motor, prefrontal, posterior parietal and inferotemporal cortex. These circuits provide the BG with the neural substrate to influence motor, cognitive, emotional and perceptual domains of behavior. We and others have argued that abnormal activity in BG loops with the cerebral cortex could lead not only to motor disorders, but also to the behavioral symptoms associated with neuropsychiatric disorders like Depression, Obsessive-Compulsive Disorder (OCD) and Tourette Syndrome (TS). The overall goal of our experiments is to link the non-motor symptoms associated with BG dysfunction to the cortical areas that are responsible for their expression. The basal ganglia can be subdivided into 3 general territories: sensorimotor, associative and limbic. This application will focus on the associative and limbic territories. Prior studies have shown that microinjections of the GABA antagonist, Bicuculline (BIC) into the associative and limbic territories of the external segment of the globus pallidus (GPe) reversibly evoke abnormal behaviors. The behavior that is evoked depends on the specific site injected within GPe. BIC injections into the associative territory evoke hyperactivity and attentional deficits, whereas injections into the limbic territory of GPe evoke excessive grooming, nail biting, and communicative gestures. We propose that the symptoms produced by a microinjection of BIC are determined by the cortical areas that are the targets of the abnormal signals from GPe. We will use transneuronal transport of rabies virus to identify the cortical areas that are interconnected with behaviorally characterized sites in GPe. We propose two sets of experiments. In the first set of experiments, we will behaviorally define sites in the associative and limbic territories of GPe using BIC micro-injections. Then, we will inject a small amount of rabies virus at the GPe site and allow retrograde transneuronal transport of the virus to label 2nd order neurons in the cerebral cortex. This approach will identify the cortical neurons that provide input to the associative and limbic territories in GPe. In a second set of experiments, we will again use micro-injections of BIC to define specific sites in the associative and limbic territories of GPe. These sites will be marked with micro-lesions. Then, we will inject rabies virus into specific areas of the cerebral cortex and allow retrograde transneuronal transport to label 3rd order neurons in GPe. We will compare the location of these GPe neurons to the marking lesions in GPe. This approach will identify cortical areas that are the targets of output from the associative and limbic territories in GPe. Together these experiments should provide new insights into the cortical areas that are responsible for the non-motor symptoms of basal ganglia dysfunction. This information may lead to new avenues for treatment of complex disorders like Depression, OCD and TS. PUBLIC HEALTH RELEVANCE The proposed studies will define the matrix of interconnections that link the basal ganglia with cortical areas in the frontal lobe. These circuits are essential for normal cognitive and affective function, and they appear to be dysfunctional in a wide variety of neuropsychiatric disorders. Thus, the results of the proposed studies could lead to new avenues for treatment of complex disorders like Depression, Obsessive-Compulsive Disorder and Tourette Syndrome.